1,4-Diazabicyclo[3.2.2]nonane-phenylisoxazole derivatives, preparation and therapeutic use thereof

ABSTRACT

Compounds corresponding to general formula (I)  
                 
 
     in which R 1 , R 2 , R 3 , R 4  and R 5  each represent, independently of one another, a hydrogen or halogen atom or a nitro, amino, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or phenyl group, it also being possible for two of these substituents in adjacent positions together to represent a methylenedioxy group, and R 6  represents a hydrogen atom or a (C 1 -C 6 )alkyl group.  
     Application in therapeutics.

[0001] The compounds of the present invention correspond to generalformula (I)

[0002] in which R₁, R₂, R₃, R₄ and R₅ each represent, independently ofone another, a hydrogen or halogen atom or a nitro, amino,trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (C₁-C₆)alkyl,(C₁-C₆)alkoxy or phenyl group, it also being possible for two of thesesubstituents in adjacent positions together to represent amethylenedioxy group, and R₆ represents a hydrogen atom or a(C₁-C₆)alkyl group.

[0003] The compounds of the invention can exist in the form of bases oraddition salts with acids.

[0004] In accordance with the invention, the compounds of generalformula (I) can be prepared by reacting 1,4-diazabicyclo[3.2.2]nonane,of the formula (II)

[0005] with a compound of general formula (IIIa) or (IIIb)

[0006] in which R₁, R₂, R₃, R₄, R₅ and R₆ are as defined above, and bythen cyclizing the compound of general formula (IV)

[0007] thus obtained, with hydroxylamine.

[0008] The preparation of 1,4-diazabicyclo-[3.2.2]nonane is described inJ. Med. Chem. 1993, 36, 2311-2320.

[0009] The compounds of general formula (IIIb) are accessible from thebismethylthio precursors (IIIa), the synthesis of which is described inthe literature, for example in Tetrahedron 1976, 32, 1779, or by analogywith this synthesis.

[0010] The stage of cyclization with hydroxylamine is described inSynthesis, 1989, 20.

[0011] The examples which will follow illustrate the preparation of somecompounds according to the invention. The elemental microanalyses andthe IR and NMR spectra confirm the structures of the compounds obtained.

[0012] The numbers shown in brackets in the titles of the examplescorrespond to those of the 1st column of Table 1 given later.

EXAMPLE 1 Compound No. 1

[0013] 4-(5-phenylisoxazol-3-yl)-1,4-diazabicyclo[3.2.2]nonaneHydrobromide 1:2.

[0014] 1.1. 1-Phenyl-3,3-bis(methylthio)prop-2-en-1-one.

[0015] 16.5 g (172 mmol) of sodium tert-butoxide in suspension in 50 mlof toluene and 30 ml of N,N-dimethylformamide are introduced into a 250ml round-bottomed flask. The medium is cooled to 4° C. in order toslowly add a mixture of 10 g (86 mmol) of acetophenone and 5.1 ml (86mmol) of carbon disulfide. The temperature is allowed to rise to ambienttemperature and the mixture is stirred for 15 h.

[0016] The mixture is again cooled to 4° C. and 10.7 ml (172 mmol) ofiodomethane are slowly added, and the reaction mixture is stirred atambient temperature for 1 h, and then refluxed for 2 h. The mixture ispoured onto ice and the aqueous phase is extracted with ethyl acetate.The organic phases are dried over sodium sulfate and are concentratedunder reduced pressure. 11.5 g of product are obtained in the form of asolid.

[0017] Melting point: 94-95° C.

[0018] 1.2. 1Phenyl-3-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(methylthio)prop-2-en-1-one.

[0019] 11 g (49 mmol) of 1-(phenyl)-3,3-bis(methylthio)prop-2-en-1-onein solution in 20 ml of ethanol and 2.06 g (16 mmol) of1,4-diazabicyclo[3.2.2]nonane are introduced into a 100 mlround-bottomed flask and the mixture is heated at 70° C. for 3 h. It iscooled to 4° C., the precipitate formed is filtered off and the filtrateis concentrated under reduced pressure. The residue is purified bychromatography on a silica gel column, elution being carried out with a90/10/1 mixture of chloroform, methanol and aqueous ammonia.

[0020] 2.3 g of product are obtained in the form of an oil.

[0021] 1.3. 4-(5-Phenylisoxazol-3-yl)-1,4-diazabicyclo-[3.2.2]nonaneHydrobromide 1:2.

[0022] 1.3 g (4.3 mmol) of1-phenyl-3-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(methylthio)prop-2-en-1-onein 40 ml of toluene and 40 ml of acetic acid are introduced into a 100ml round-bottomed flask. A solution of 1.2 g (17.2 mmol) ofhydroxylamine hydrochloride and 1.2 g (14.6 mmol) of sodium acetate in 5ml of water and 10 ml of ethanol is then added and the mixture isrefluxed for 24 h. The solvents are removed under reduced pressure andthe residue is purified by chromatography on a silica gel column,elution being carried out with a 90/10/1 mixture of chloroform, methanoland aqueous ammonia.

[0023] 0.45 g of product is obtained in the form of an oil, which isdissolved in 10 ml of acetone in order to add 0.7 ml of a 5.7 N solutionof hydrobromic acid in acetic acid. The crystals obtained are collectedby filtration; 0.5 g of product is obtained.

[0024] Melting point: 253-255° C.

EXAMPLE 2 Compound No. 4

[0025] 4-[5-(3-methylphenyl)isoxazol-3-yl]-1,4-diazabicyclo[3.2.2]nonaneHydrobromide 1:2.

[0026] 2.1. 1-(3-Methylphenyl)-3,3-bis(methylthio)prop-2-en-1-one.

[0027] 7.2 g (74 mmol) of sodium tert-butoxide in suspension in 40 ml oftoluene and 20 ml of N,N-dimethylformamide are introduced into a 250 mlround-bottomed flask. The medium is cooled to 4° C. in order to slowlyadd a mixture of 5 g (37 mmol) of 3-methylacetophenone and 2.2 ml (37mmol) of carbon disulfide. The temperature is allowed to rise to ambienttemperature and the mixture is stirred for 15 h.

[0028] The mixture is again cooled to 4° C., 4.6 ml (74 mmol) ofiodomethane are slowly added, and the reaction mixture is stirred atambient temperature for 1 h and then at reflux for 2 h. The mixture ispoured onto ice and the aqueous phase is extracted with ethyl acetate.The organic phases are dried over sodium sulfate and are concentratedunder reduced pressure. 8.9 g of product are obtained in the form of asolid.

[0029] Melting point: 81-82° C.

[0030] 2.2.1-(3-Methylphenyl)-3-(methylsulfinyl)-3-(methylthio)prop-2-en-1-one.

[0031] 8.6 g (36 mmol) of1-(3-methylphenyl)-3,3-bis(methylthio)prop-2-en-1-one in solution in 100ml of chloroform are introduced into a 250 ml round-bottomed flask. Themixture is cooled to 4° C. and 8.9 g (36 mmol) of 3-chloroperbenzoicacid are added portionwise and the mixture is stirred at ambienttemperature for 15 h.

[0032] The solvent is concentrated under reduced pressure and theresidue is purified by chromatography on a silica gel column, elutionbeing carried out with a 70/30 to 80/20 mixture of cyclohexane and ethylacetate.

[0033] 3.8 g of product are obtained in the form of a solid.

[0034] Melting point: 126-127° C.

[0035] 2.3.1-(3-Methylphenyl)-3-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(methylthio)prop-2-en-1-one

[0036] 2.1 g (8.25 mmol) of1-(3-methylphenyl)-3-(methylsulfinyl)-3-(methylthio)prop-2-en-1-one insolution in 50 ml of ethanol and 0.35 g (2.8 mmol) of1,4-diazabicyclo[3.2.2]nonane are introduced into a 100 mlround-bottomed flask and the mixture is heated at 70° C. for 1.5 h andis cooled to 4° C.

[0037] The precipitate formed is separated by filtration and thefiltrate is concentrated under reduced pressure. The residue is purifiedby chromatography on a silica gel column, elution being carried out witha 90/10/1 mixture of chloroform, methanol and aqueous ammonia.

[0038] 0.77 g of product is obtained in the form of an oil.

[0039] 2.44-[5-(3-Methylphenyl)isoxazol-3-yl]-1,4-diazabicyclo[3.2.2]nonaneHydrobromide 1:2.

[0040] 0.54 g (1.7 mmol) of1-(3-methylphenyl)-3-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(methylthio)prop-2-en-1-onein 15 ml of toluene and 15 ml of acetic acid is introduced into a 100 mlround-bottomed flask. A solution of 0.47 g (6.8 mmol) of hydroxylaminehydrochloride and 0.56 g (6.8 mmol) of sodium acetate in 5 ml of waterand 10 ml of ethanol is then added and the mixture is refluxed for 2 h.The solvents are evaporated under reduced pressure and the residue ispurified by chromatography on a silica gel column, elution being carriedout with a 90/10/1 mixture of chloroform, methanol and aqueous ammonia.

[0041] 0.3 g of product is obtained in the form of an oil, which isdissolved in 5 ml of acetone in order to add 0.37 ml of a 5.7 N solutionof hydrobromic acid in acetic acid. The crystals obtained are collectedby filtration and 0.35 g of product is obtained.

[0042] Melting point: 238-241° C.

EXAMPLE 3 Compound No. 3

[0043]4-[5-(3-Trifluoromethylphenyl)isoxazol-3-yl]-1,4-diazabicyclo[3.2.2]nonaneHydrobromide 1:2.

[0044] 3.11-(3-Trifluoromethylphenyl)-3,3-bis(methylthio)prop-2-en-1-one

[0045] This compound is obtained from 3-trifluoromethylacetophenone bythe method described in stage 2.1.

[0046] Melting point: 88-89° C.

[0047] 3.21-(3-Trifluoromethylphenyl)-3-(methylsulfinyl)-3-(methylthio)prop-2-en-1-one.

[0048] This compound is obtained from1-(3-trifluoromethylphenyl)-3,3-bis(methylthio)prop-2-en-1-one by themethod described in stage 2.2.

[0049] Melting point: 124-125° C.

[0050] 3.31-(3-Trifluoromethylphenyl)-3-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(methylthio)prop-2-en-1-one.

[0051] This compound is obtained from1-(3-trifluoromethylphenyl)-3-(methylsulfinyl)-3-(methylthio)prop-2-en-1-oneby the method described in stage 2.3.

[0052] The compound is obtained in the form of an oil.

[0053] 3.44-[5-(3-Trifluoromethylphenyl)isoxazol-3-yl]-1,4-diazabicyclo[3.2.2]nonaneHydrobromide 1:2.

[0054] The compound is obtained from1-(3-trifluoromethylphenyl)-3-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(methylthio)prop-2-en-1-oneby the method described in stage 2.4.

[0055] Melting point: 233-234° C.

EXAMPLE 4 Compound No. 5

[0056]4-[5-(3-Methoxyphenyl)isoxazol-3-yl]-1,4-diazabicyclo[3.2.2]nonaneHydrobromide 1:1.

[0057] 4.1 1-(3-Methoxyphenyl)-3,3-bis(methylthio)prop-2-en-1-one.

[0058] This compound is obtained from 3-methoxyacetophenone by themethod described in stage 2.1.

[0059] Melting point: 59-60° C.

[0060] 4.21-(3-Methoxyphenyl)-3-(methylsulfinyl)-3-(methylthio)prop-2-en-1-one.

[0061] This compound is obtained from1-(3-methoxyphenyl)-3,3-bis(methylthio)prop-2-en-1-one by the methoddescribed in stage 2.2.

[0062] Melting point: 119-121° C.

[0063] 4.31-(3-Methoxyphenyl)-3-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(methylthio)prop-2-en-1-one.

[0064] This compound is obtained from1-(3-methoxyphenyl)-3-(methylsulfinyl)-3-(methylthio)prop-2-en-1-one bythe method described in stage 2.3. The product is obtained in the formof an oil.

[0065] 4.44-[5-(3-Methoxyphenyl)isoxazol-3-yl]-1,4-diazabicyclo[3.2.2]nonaneHydrobromide 1:1.

[0066] This compound is obtained from1-(3-methoxyphenyl)-3-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(methylthio)prop-2-en-1-oneby the method described in stage 2.4.

[0067] Melting point: 240-242° C.

EXAMPLE 5 Compound No. 6

[0068] 4-[5-(2-Bromophenyl)isoxazol-3-yl]-1,4-diazabicyclo[3.2.2]nonane.

[0069] 5.1 1-(2-Bromophenyl)-3,3-bis(methylthio)prop-2-en-1-one.

[0070] This compound is obtained from 2-bromoacetophenone by the methoddescribed in stage 2.1.

[0071] Melting point: 135-136° C.

[0072] 5.21-(2-Bromophenyl)-3-(methylsulfinyl)-3-(methylthio)prop-2-en-1-one.

[0073] This compound is obtained from1-(2-bromophenyl)-3,3-bis(methylthio)prop-2-en-1-one by the methoddescribed in stage 2.2.

[0074] The product is obtained in the form of an amorphous solid.

[0075] 5.31-(2-Bromophenyl)-3-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(methylthio)prop-2-en-1-one.

[0076] This compound is obtained from1-(2-bromophenyl)-3-(methylsulfinyl)-3-(methylthio)prop-2-en-1-one bythe method described in stage 2.3. The product is obtained in the formof an oil.

[0077] 5.44-[5-(2-Bromophenyl)isoxazol-3-yl]-1,4-diazabicyclo[3.2.2]nonane.

[0078] This compound is obtained from1-(2-bromophenyl)-3-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(methylthio)prop-2-en-1-oneby the method described in stage 2.4, but the product is isolated in theform of a free base.

[0079] Melting point: 107-108° C.

EXAMPLE 6 Compound No. 7

[0080] 4-[5-(4-Fluorophenyl)isoxazol-3-yl]-1,4-diazabicyclo[3.2.2]nonaneHydrobromide 1:2.

[0081] 6.1 1-(4-Fluorophenyl)-3,3-bis(methylthio)prop-2-en-1-one.

[0082] This compound is obtained from 4-fluoroaceto-phenone by themethod described in stage 2.1.

[0083] Melting point: 87-89° C.

[0084] 6.21-(4-Fluorophenyl)-3-(methylsulfinyl)-3-(methylthio)prop-2-en-1-one.

[0085] This compound is obtained from1-(4-fluorophenyl)-3,3-bis(methylthio)prop-2-en-1-one by the methoddescribed in stage 2.2.

[0086] Melting point: 145-146° C.

[0087] 6.31-(4-Fluorophenyl)-3-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(methylthio)prop-2-en-1-one.

[0088] This compound is obtained from1-(4-fluorophenyl)-3-(methylsulfinyl)-3-(methylthio)prop-2-en-1-one bythe method described in stage 2.3. The product is obtained in the formof an oil.

[0089] 6.44-[5-(4-Fluorophenyl)isoxazol-3-yl]-1,4-diazabicyclo[3.2.2]nonaneHydrobromide 1:2.

[0090] This compound is obtained from1-(4-fluorophenyl)-3-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(methylthio)prop-2-en-1-oneby the method described in stage 2.4.

[0091] Melting point: 236-238° C.

EXAMPLE 7 Compound No. 10

[0092] 4-[5-(4-Methylphenyl)isoxazol-3-yl]-1,4-diazabicyclo[3.2.2]nonanehydrobromide 1:2.

[0093] 7.1 1-(4-Methylphenyl)-3,3-bis(methylthio)prop-2-en-1-one.

[0094] This compound is obtained from 4-methylacetophenone by the methoddescribed in stage 2.1.

[0095] Melting point: 103-104° C.

[0096] 7.21-(4-Methylphenyl)-3-(methylsulfinyl)-3-(methylthio)prop-2-en-1-one.

[0097] This compound is obtained from1-(4-methylphenyl)-3,3-bis(methylthio)prop-2-en-1-one by the methoddescribed in stage 2.2.

[0098] Melting point: 170-172° C.

[0099] 7.31-(4-Methylphenyl)-3-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(methylthio)prop-2-en-1-one.

[0100] This compound is obtained from1-(4-methylphenyl)-3-(methylsulfinyl)-3-(methylthio)prop-2-en-1-one bythe method described in stage 2.3.

[0101] The product is obtained in the form of an oil.

[0102] 7.44-[5-(4-Methylphenyl)isoxazol-3-yl]-1,4-diazabicyclo[3.2.2]nonaneHydrobromide 1:2.

[0103] This compound is obtained from1-(4-methylphenyl)-3-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(methylthio)prop-2-en-1-oneby the method described in stage 2.4.

[0104] Melting point: 283-289° C.

[0105] The chemical structures and the physical properties of somecompounds according to the invention are illustrated in the table below.TABLE

(I) No. R₁ R₂ R₃ R₄ R₅ R₆ Salt M.p.° C. 1 H H H H H H HBr 2:1 253-255 2Cl H H H H H HBr 1:1 253-254 3 H CF₃ H H H H HBr 2:1 233-234 4 H CH₃ H HH H HBr 2:1 238-241 5 H OCH₃ H H H H HBr 1:1 240-242 6 Br H H H H H —107-108 7 H H F H H H HBr 2:1 236-238 8 CH₃ H H H H H HBr 2:1 227-232 9H H OCH₃ H H H HBr 2:1 224-230 10 H H CH₃ H H H HBr 2:1 283-289 11 HOCF₃ H H H H HBr 2:1 210-213 12 OCH₃ H H H H H HBr 2:1 201-202 13 H HC₆H₅ H H H HBr 2:1 291-294 14 OCH₃ H H H OCH₃ H HBr 2:1 174-175 15 HOCH₂O H H H HBr 2:1 245-248

[0106] The compounds of the invention have been the subject of testswhich have demonstrated their advantage as therapeutic substances.

[0107] Thus, they have been identified with regard to their affinity fornicotinic receptors comprising the α₇ subunit according to the methodsdescribed by Marks and Collins in Mol. Pharmacol. 1982, 22, 554 and byMarks et al., in Mol. Pharmacol. 1986, 30, 427.

[0108] Male OFA rats weighing 150 to 200 g are decapitated and theentire brain is quickly removed, homogenized using a Polytron™ mill in15 volumes of a 0.32 M sucrose solution at 4° C. and then centrifuged at1000 g for 10 min. The pellet is eliminated and the supernatant iscentrifuged at 8000 g for 20 min at 4° C. The pellet is recovered andhomogenized using a Polytron™ mill in 15 volumes of bubbly-distilledwater at 4° C., and then centrifuged at 8000 g for 20 min. The pellet iseliminated and the supernatant and the layer of skin (“buffy coat”) arecentrifuged at 40 000 g for 20 min. The pellet is recovered, resuspendedwith 15 volumes of doubly-distilled water at 4° C. and centrifuged onceagain at 40 000 g for 20 min before being stored at −80° C.

[0109] On the day of the experiment, the tissue is slowly thawed and issuspended in 5 volumes of buffer. 150 μl of this membrane suspension arepreincubated at 37° C. for 30 min, in the dark, in the presence orabsence of the compound to be tested. The membranes are then incubatedfor 60 min at 37° C., in the dark, in the presence of 50 μl of 1 nM[³H]α-bungarotoxin in a final volume of 250 μl of 20 mM HEPES buffer.The reaction is stopped by filtration through Whatman GF/C™ filterspretreated for 3 h with 0.05% polyethyleneimine. The filters are rinsedwith two times 5 ml of buffer at 4° C. and the radioactivity retained oneach filter is measured by liquid scintigraphy. The nonspecific bindingin the presence of 1 μM α-bungarotoxin is determined; the nonspecificbinding represents approximately 60% of the total binding recovered inthe filter. For each concentration of compound studied, the percentageinhibition of the specific binding of [³H]α-bungarotoxin is determined,and the IC₅₀, the concentration of compound which inhibits 50% of thespecific binding, is calculated.

[0110] The IC₅₀ values of the acutest compounds of the invention liebetween 0.02 and 0.5 μM.

[0111] The compounds of the present invention were also studied withregard to their affinity for nicotinic receptors comprising the α₄β₂subunit according to the methods described by Anderson and Arneric inEur. J. Pharmacol. 1994, 253, 261 and by Hall et al., in Brain Res.1993, 600, 127.

[0112] Male Sprague-Dawley rats weighing 150 to 200 g are decapitatedand the entire brain is quickly removed, homogenized in 15 volumes of a0.32 M sucrose solution at 4° C. and then centrifuged at 1000 g for 10min. The pellet is removed and the supernatant is centrifuged at 20 000g for 20 min at 4° C. The pellet is recovered and homogenized using aPolytron™ mill and 15 volumes of doubly-distilled water at 4° C., and isthen centrifuged at 8000 g for 20 min. The pellet is removed and thesupernatant and the layer of skin (“buffy coat”) are centrifuged at 40000 g for 20 min, the pellet is recovered, suspended in 15 ml ofdoubly-distilled water and centrifuged once again at 40 000 g beforebeing stored at −80° C.

[0113] On the day of the experiment, the tissue is slowly thawed and issuspended in 3 volumes of buffer. 150 μl of this membrane suspension areincubated at 4° C. for 120 min in the presence of 100 μl of 1 nM[³H]-cytisine in a final volume of 500 μl of buffer, in the presence orabsence of compound to be tested. The reaction is stopped by filtrationthrough Whatman GF/B™ filters pretreated with polyethyleneimine, thefilters are rinsed with two times 5 ml of buffer at 4° C., and theradioactivity retained on the filter is measured by liquid scintigraphy.The nonspecific binding in the presence of 10 μM (−)-nicotine isdetermined; the nonspecific binding represents 75 to 85% of the totalbinding recovered from the filter. For each concentration of compoundstudied, the percentage inhibition of the specific binding of[³H]-cytisine is determined, and then the IC₅₀, the concentration ofcompound which inhibits 50% of the specific binding, is calculated.

[0114] The IC₅₀ values of the compounds of the invention are of theorder of 10 μM.

[0115] The preceding results show that the compounds of the inventionare ligands which are selective for α₇ subunits, relative to α₄β₂subunits of the nicotinic receptor.

[0116] The results of the various tests suggest the use of the compoundsin the treatment or prevention of disorders related to a dysfunction ofnicotinic receptors, in particular in the central nervous system.

[0117] These disorders comprise cognitive impairments, more specificallymemory impairments, and also impairments of attention, related toAlzheimer's disease, to pathological aging (Age Associated MemoryImpairment, AAMI), to Parkinsonian syndrome, to trisomie 21 (Down'ssyndrome), to Korsakoff's alcoholic syndrome or to vascular dementias(multi-infarct dementia, MDI).

[0118] The compounds of the invention might also be of use in thetreatment of motor disorders observed in Parkinson's disease or otherneurological diseases, such as Huntington's chorea, Tourette's syndrome,tardive dyskinesia and hyperkinesia.

[0119] The compounds of the invention may also constitute a curative orsymptomatic treatment of strokes and cerebral-hypoxyic episodes. Theymay be used in the case of psychiatric pathologies: schizophrenia,depression, anxiety, panic attacks, obsessive-compulsive behavior.

[0120] They can prevent symptoms due to tobacco withdrawal, to alcoholwithdrawal, and to withdrawal of dependency-inducing substances such ascocaine, LSD, cannabis or benzodiazepines.

[0121] For this reason, a subject of the present invention is alsopharmaceutical compositions containing an effective dose of at least onecompound according to the invention, in the form of a base or apharmaceutically acceptable salt or solvate, and as a mixture, ifappropriate, with suitable excipients.

[0122] Said excipients are chosen according to the pharmaceutical formand the method of administration desired.

[0123] The pharmaceutical compositions according to the invention maythus be intended for oral, sublingual, subcutaneous, intramuscular,intravenous, topical, intratracheal, intranasal, transdermal, rectal orintraoccular administration.

[0124] The unit administration forms can be, for example, tablets,gelatin capsules, granules, powders, solutions or suspensions to betaken orally or to be injected, transdermal patches or suppositories.Ointments, lotions and eye lotions can be envisaged for topicaladministration.

[0125] Said unit forms contain a dose to allow daily administration of0.01 to 20 mg of active principle per kg of body weight, depending onthe pharmaceutical form.

[0126] To prepare tablets, a pharmaceutical vehicle, which can becomposed of diluents, such as, for example, lactose, microcrystallinecellulose, starch, and of formulation adjuvants, such as binders(polyvinylpyrrolidone, hydroxypropylmethylcellulose, etc), flow agentssuch as silica, or lubricants such as magnesium stearate, stearic acid,glycerol tribehenate or sodium stearyl fumarate, is added to themicronized or unmicronized active principle. Wetting agents orsurfactants, such as sodium lauryl sulfate, can also be added.

[0127] The preparation techniques can be direct tableting, drygranulation, wet granulation or hotmelt.

[0128] The tablets can be bare, coated with sugar, for example withsucrose, or coated with various polymers or other suitable materials.They can be designed to allow rapid, delayed or sustained release of theactive principle by virtue of polymer matrices or of specific polymersused in the coating.

[0129] To prepare gelatin capsules, the active principle is mixed withdry pharmaceutical vehicles (simple mixing, wet or dry granulation, orhotmelt), or liquid or semisolid pharmaceutical vehicles.

[0130] The gelatin capsules can be hard or soft, and uncoated or coatedwith a thin film, so as to have rapid, sustained or delayed activity(for example for an enteric form).

[0131] A composition in the form of a syrup or elixir or foradministration in the form of drops can comprise the active principletogether with a sweetener, preferably a calorie-free sweetener,methylparaben or propylparaben as antiseptic, an agent to impart flavorand a dye.

[0132] The water-dispersible powders and granules can comprise theactive principle as a mixture with dispersing agents or wetting agents,or dispersing agents such as polyvinylpyrrolidone, as well as-withsweeteners and flavor enhancers.

[0133] For rectal administration, use is made of suppositories preparedwith binders which melt at rectal temperature, for example cocoa butteror polyethylene glycols.

[0134] For parenteral administration, use is made of aqueoussuspensions, isotonic saline solutions or injectable sterile solutionscontaining pharmacologically compatible dispersing agents and/or wettingagents, for example propylene glycol or butylene glycol.

[0135] The active principle can also be formulated in the form ofmicrocapsules, optionally with one or more carriers or additives, orelse with a polymer matrix or with a cyclodextrin (transdermal patches,sustained-release forms).

[0136] The topical compositions according to the invention comprise amedium compatible with the skin. They can be provided in particular inthe form of aqueous, alcoholic or aqueous/alcoholic solutions, of gels,of water-in-oil or oil-in-water emulsions having the appearance of acream or of a gel, of microemulsions, of aerosols, or else in the formof vesicular dispersions containing ionic and/or nonionic lipids. Thesepharmaceutical forms are prepared according to the methods conventionalin the fields under consideration.

[0137] Finally, the pharmaceutical compositions according to theinvention can comprise, in addition to a compound of general formula(I), other active principles which can be used in the treatment of thedisorders and diseases indicated above.

1. A compound corresponding to general formula (I)

in which R₁, R₂, R₃, R₄ and R₅ each represent, independently of oneanother, a hydrogen or halogen atom or a nitro, amino, trifluoromethyl,trifluoromethoxy, cyano, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy or phenylgroup, it also being possible for two of these substituents in adjacentpositions together to represent a methylenedioxy group, and R₆represents a hydrogen atom or a (C₁-C₆)alkyl group, in the form of abase or of an addition salt with an acid.
 2. A method for preparing acompound as claimed in claim 1, characterized in that1,4-diazabicyclo[3.2.2]nonane is reacted with a compound of generalformula (IIIa) or (IIIb)

in which R₁, R₂, R₃, R₄, R₅ and R₆ are as defined in claim 1, and thenthe compound of general formula (IV)

thus obtained is cyclized with hydroxylamine.
 3. A medicament,characterized in that it consists of a compound as claimed in claim 1.4. A pharmaceutical composition, characterized in that it comprises acompound as claimed in claim 1, in combination with an excipient.